Renal injury biomarkers as biomarkers for acute hepatic porphyria (ahp)

Abstract

The disclosure provides biomarkers for diagnosis and monitoring of acute hepatic porphyria (AHP). The disclosure further provides methods for selection of agents for treatment of AHP using the biomarkers. The disclosure further provides kits for practicing the methods provided herein.

1 . A method of treating a human subject having acute hepatic porphyria (AHP), comprising:
 responsive to a determination of an elevated level of a biomarker in a subject relative to a reference level, administering to the subject a therapeutic agent that reduces expression of 5′-aminolevulinic acid synthase 1 (ALAS1),   thereby treating the subject.   
     
     
         2 . A method of treating a human subject having, or at risk of having, AHP, comprising:
 obtaining or having obtained a biological sample from the subject,   performing or having performed an assay to determine the level of a biomarker in the biological sample,   and, if the subject has an elevated level of the biomarker relative to a reference value, administering to the subject a therapeutic agent that reduces expression of ALAS1,   thereby treating the subject.   
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 2 , wherein the biomarker is selected from the group consisting of KIM1, APLP1, MMP7, NGAL, CST3, and CHI3L1. 
     
     
         5 . The method of  claim 2 , wherein the biomarker is a renal injury biomarker. 
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 2 , wherein the therapeutic agent that reduces the expression of ALAS1 is a nucleic acid therapeutic. 
     
     
         8 . The method of  claim 7 , wherein the nucleic acid therapeutic is an RNAi agent or an antisense oligonucleotide. 
     
     
         9 . The method of  claim 7 , wherein the nucleic acid therapeutic is givosiran. 
     
     
         10 . The method of  claim 2 , wherein the subject:
 (i) is a chronic high excreter;   (ii) has recurring acute attacks;   (iii) has an elevated level of ALA and/or PBG;   (iv) has a mutation associated with AHP;   (v) has a history of renal impairment;   (vi) has been diagnosed with a renal injury; and/or   (vii) has a reduced estimated glomerular filtration rate (eGFR).   
     
     
         11 . (canceled) 
     
     
         12 . The method of  claim 2 , wherein the subject:
 (i) has not been diagnosed with AHP;   (ii) has not been diagnosed as having a porphyria;   (iii) does not meet the diagnostic criteria for AHP; and/or   (iv) does not have a mutation associated with AHP.   
     
     
         13 .- 20 . (canceled) 
     
     
         21 . The method of  claim 2 , wherein the reference level is a healthy control level or an earlier level in the same subject. 
     
     
         22 . The method of  claim 2 , wherein the level of the biomarker is increased by at least 2-fold, compared to the reference level of the biomarker. 
     
     
         23 . The method of  claim 2 , wherein the subject is being treated with a second therapeutic agent. 
     
     
         24 . The method of  claim 23 , wherein the second therapeutic agent comprises a heme product, glucose, dextrose, or combinations thereof. 
     
     
         25 . The method of  claim 23 , further comprising discontinuation of treatment with the second therapeutic agent when the subject has the elevated level of the biomarker. 
     
     
         26 . The method of  claim 2 , wherein the level is determined in a subject sample selected from blood, plasma, serum, urine, or stool. 
     
     
         27 . The method of  claim 2 , wherein the subject is further suffering from one or more symptoms associated with AHP. 
     
     
         28 .- 53 . (canceled) 
     
     
         54 . An in vitro method of diagnosing AHP in a subject, the method comprising:
 (a) determining the level of a biomarker in a sample from the subject;   (b) comparing the level of the biomarker determined in step (a) to a reference level of the biomarker, e.g., renal injury biomarker; and   (c) assessing whether the subject suffers from AHP, wherein an increase in the level of the biomarker determined in step (a) as compared to the reference level of the biomarker, e.g., renal injury biomarker, is indicative of the subject suffering from AHP.   
     
     
         55 . The method of  claim 54 , wherein the biomarker is chosen from one or more of KIM1, APLP1, MMP7, NGAL, CST3, or CHI3L1. 
     
     
         56 . The method of  claim 54 , wherein the biomarker is a renal injury biomarker. 
     
     
         57 . The method of  claim 56 , wherein the renal injury biomarker is chosen from one or more (e.g., 2, 3, 4, or all) of KIM1, APLP1, MMP7, NGAL, CST3, or CHI3L1. 
     
     
         58 . The method of  claim 54 , wherein the subject:
 (i) has been diagnosed with AHP;   (ii) has an elevated level of ALA and/or PBG;   (iii) has been diagnosed with a renal injury; or   (iv) has a reduced estimated glomerular filtration rate (eGFR).   
     
     
         59 . (canceled) 
     
     
         60 . The method of  claim 54 , wherein the subject has a mutation associated with AHP, or wherein the subject does not have a mutation associated with AHP. 
     
     
         61 .- 63 . (canceled) 
     
     
         64 . The method of  claim 54 , wherein the reference level is a healthy control level or an earlier level in the same subject. 
     
     
         65 . The method of  claim 54 , wherein the level of the biomarker is increased by at least 2-fold, compared to the reference level of the biomarker. 
     
     
         66 . The method of  claim 54 , wherein the subject is being treated with a therapeutic agent that reduces the expression of ALAS1. 
     
     
         67 .- 91 . (canceled)